Tissue defects resulting from trauma and degeneration are significant challenges in medicine as current tissue replacement technologies are based on end point treatments that do not regenerate the tissue. Musculoskeletal tissues are of significant importance as these tissues support bodily movement, function, and overall human physical activity. When these tissues undergo significant trauma or undergo degeneration due to abnormal use or overuse, they require external intervention to restore normal function. Particular challenges for musculoskeletal injuries include cartilage tissue degeneration. Within the human body there exist three types of cartilage namely elastic, hyaline (articular) and fibrocartilage. Elastic cartilage is the cartilage present in the outer ear, larynx, and epiglottis, while hyaline (articular) and fibrocartilage are found primarily within joints such as the knee. Hyaline or articular cartilage is a type of cartilage found on joint surfaces on the end of long bones. Fibrocartilage consists of fibrous and cartilaginous tissue and is primarily found in within the annulus fibrosus of intervertebral discs, and meniscus of the knee joint. Both articular and fibrocartilage provide a bearing surface that distributes load for force transmission and act as a shock absorber for joints. However both articular and fibrocartilage can undergo degeneration following abnormal loading or overloading in joints such as the knee, resulting in the formation of tears and/or lesions. These deformities are based on the deterioration of the cartilage surface based on a thinning of the cartilage surface due to excessive wear. Unlike other musculoskeletal tissues that are able to undergo some regeneration (i.e. bone) cartilage lacks the intrinsic regenerative capacity for repair based on the tissue's low cellularity and the lack of vascularization, nerves, and lymphatic system. Without treatment, cartilage lesions are known to result in osteoarthritis (OA), the most common joint disease in the world. OA is characterized by fibrillation or wearing of the cartilage surface resulting in articular cartilage degradation, joint pain, and eventually requiring surgical intervention. Total joint replacement (TJR) is currently the only treatment for end stage OA. TJR operations have been projected to continue to escalate based on the aging baby boomer population, increase in average lifespan, and earlier onset of obesity in adults, and increasing activity level of afflicted patients. Current limitations with TJR are its limited lifespan, loss of quality of life (i.e. activity), overall cost (median cost of $28,000/patient), and end point nature. TJR is currently the only treatment for end stage OA with a current U.S. market size of $17 billion. The TJR market size has been projected to grow to $100 billion by 2030. Despite the significant projection in market size increase, regenerative medicine strategies are starting to emerge as a defining treatment to curtail end stage OA and replace damaged cartilage to prevent further cartilage degradation.
Articular Cartilage Regeneration
Some embodiments of the present invention allow for articular cartilage regeneration. Aforementioned, articular cartilage is the cartilage that covers the end of long bones (e.g. tibia, femur, etc.) and acts as a shock absorber and provides a smooth frictionless surface for articulation. Articular cartilage exhibits anisotropic mechanical properties as a result of depth dependent differences in the density and structural arrangement of its extracellular matrix, which consists predominantly of proteoglycan molecules retained within a fibrillar type II collagen meshwork. The fibrillar collagen meshwork provides mechanical reinforcement and is comprised of four zones, namely the superficial, transitional, radial, and calcified cartilage zones. As a function of these zones, collagen fibers vary in their alignment, progressing from parallel in the superficial region, to random in the middle zone and finally orientating perpendicular to the subchondral bone surface in the deep and calcified cartilage zone. This anisotropic fiber orientation contributes to depth-dependent or zonal mechanical properties in terms of ultimate tensile strength and tensile modulus. From a functional and simplified perspective, cartilage can be classified into three main regions, the superficial zone which exhibits a high tensile strength and low coefficient of friction to maintain smooth articulation, a dense extracellular matrix region which contributes to the compressive mechanical properties by providing a high osmotic swelling pressure within the tissue based on the abundance of proteoglycan molecules and the counterbalance with water, and the calcified cartilage interface that adheres cartilage to bone.
Clinical articular cartilage restoration is an evolving field where established and emerging replacement strategies are being performed within the clinical setting to treat chondral lesions as a means to restore articular cartilage. Current cartilage restorative procedures include bone marrow stimulation, fresh osteochondral allografts (donor tissue), osteochondral autografts (patient's tissue), and autologous chondrocyte implantation (ACI). Despite these numerous techniques there stills lies abundant controversy regarding treatment method. In practice, a given method is selected at the discretion of the orthopedic surgeon based on the size of the defect, location, as well as number of previous surgeries. The ACI technique was first reported in 1997 and involves implanting a patient's own chondrocytes at the defect site. In this technique a biopsy of healthy articular cartilage is arthroscopically harvested from a low or non-load bearing location and the cartilage is enzymatically treated to isolate the patient's own chondrocytes. From this initial cell population of a few hundred thousand, the chondrocytes are expanded to more than 10 million. Following expansion, the cells are injected into the cartilage defect beneath a periosteum patch. The periosteum is a fibrous membrane located on the patient's long bones (e.g. tibia) that is harvested by the surgeon, sutured over the defect site adjacent to the surrounding healthy cartilage, and the expanded cells are injected beneath the membrane.
While classical ACI treatment utilizes a periosteum membrane to retain a cell suspension, certain embodiments of the present invention propose the isolation, expansion, and seeding of expanded cells into implantable devices. Such devices are meant to act as a carrier of the chondrocytes and help with attachment, provide temporary mechanical support, and reside in the tissue defect site. Re-operation rates for classical periosteum-based ACI are up to nearly 40% with complications ranging from graft failure, graft delamination, tissue hypertrophy, and tissue adhesion, among others. Approximately 90% of patients with complications experience transplant hypertrophy, lack of integration with surrounding cartilage, inferior cartilage regeneration, and/or graft delamination. Specific advantages for at least some of the devices and methods for ACI treatment disclosed herein over periosteum-based ACI treatments may include, for example, the removal of specific complications including patient morbidity at the harvest site, variability in periosteum physical properties (based on anatomical location, harvest technique, thickness, regenerative capacity), as well as reoperation rates caused by periosteum failure and poor tissue growth. As described herein, device based ACI also features enhanced fixation mechanisms to prevent delamination and support integration of the device into surrounding tissues, in certain embodiments.
One challenge in cartilage restorative therapies lies in generating improved tissue durability and functional improvement. Aforementioned articular cartilage is a highly organized, fiber-reinforced tissue that provides a low-friction and wear-resistant bearing surface comprised of four main zones, the superficial, transitional, radial, and calcified cartilage zones. It is believed that the superficial zone provides a smooth lubricating surface and high tensile mechanics, the transitional and radial zones are comprised of bulk proliferating and compressive zone where the majority of its compressive properties are generated, and the calcified cartilage zone is the cartilage/bone interface which anchors cartilage to bone and allows for force transmission. The mechanical properties of this tissue vary based on the specific zone of cartilage; bulk properties of articular cartilage include a tensile modulus (stiffness) of 5-25.5 MPa and compressive modulus of 0.1-2 MPa, and a smooth articulating surface with surface roughness (Ra) 0.1-1 μm and frictional coefficient (μ) of 0-0.5.
In some embodiments of the present invention, one or more factors for selecting and designing the device include, for example, 1) the type of tissue to be generated (articular cartilage possesses zonal organization and unique architecture that is associated with its overall function), 2) the need for sufficient integration with bone, 3) whether a smooth and/or lubricating surface is desired, 4) optionally, a highly porous region for extracellular matrix deposition, 5) the possibility for an open-edge porous structure to allow lateral integration with the native tissue, 6) the need for adhesion to subchondral bone, 7) desired mechanical properties such as tension, compression, shear, and coefficients of friction, and 8) the availability of improved attachment methodology for adhering the device into the tissue (including for example transosseos fixation of one fabric) and suturing of the other fabric to the surrounding healthy cartilage tissue. The fixation of the device in vivo may assist with its placement and performance, in some embodiments, and there are a variety of attachment mechanisms available. The additional use of tissue adhesives is also conceived. For example, a fabric fixation point can be adhered to tissue near the placement site employing a suitable tissue adhesive. Suitable tissue adhesives include, but are not limited to, fibrin glue, cyanoacrylate, thrombin, transglutaminases, and gelatin-based adhesives, amongst others. Tension-based fixation can employ fabric fixation points which can act as suture attachments or fixation points that provide tension to the device through a downward (boneward) force attached to or through bone. Shear-based fixation involves fixating a fabric to the surrounding tissue and can include a fabric overlap to act as a plug to enhance the integration between the surrounding healthy cartilage tissue and the device. The fabric overlap can be substantially uniform around the circumference of the device, or in some regions of the fabric, the overlap can vary, with some regions having more and other regions having less of an overlap, or none at all. In some cases, one or more properties of an implantable device made according to the present invention can be guided by reference to the properties exhibited by the natural tissue the device will replace or repair.
Meniscus Tissue Regeneration
Further embodiments of the present invention allow for meniscus tissue regeneration. The menisci are two wedge-shaped semilunar discs of fibrocartilageneous tissue. Menisci are functionally a dynamical tissue where they aid in force distribution, stability, and provide lubrication surfaces between the tibial plateau and femoral condyles. The menisci are attached to the transverse ligaments, the joint capsule, the medial collateral ligament and the menisco-femoral ligament. Based on their functional role, intact menisci occupy 60% of the contact area between the articular cartilage of the femoral condyles and the tibial plateau, and transmit greater than 50% of the axial load applied in the joint. The menisci are able to undergo high degrees of loading based on the arrangement of extracellular matrix components (mainly type I collagen in dense bundles in a circumferential pattern) which prevent radial extrusion of the tissue. Based on the circumferential orientation of the collagen bundles, this tissue exhibits anisotropic tensile properties with a tensile modulus of 100-300 MPa in the circumferential direction and approximately 10-30 MPa in the radial direction. The overall aggregate modulus of the tissue is in the range of 100-200 kPa. Due to its unique wedge-shape, the menisci are well suited for distributing loads from the curved femoral condyles to the flat tibial plateau. Menisci also demonstrate zonal organization varying from an avascular to vascular zones radiating from the inside-out; these transition zones are known as the white-white zone (avascular), red-white zone (interface), and red-red zone (vascular).
The overall pathophysiology of this tissue is significant as it accounts for the most surgical procedures performed by orthopedic surgeons. Meniscal tears are classified based on the location, thickness, and overall stability of the joint and include zonal location (i.e. red-red) as well as the type of tear. For most meniscal tears, partial meniscus removal is common therapy though it is well known that even partial removal will likely result in accelerated degeneration of articular cartilage, resulting in osteoarthritis.
Certain embodiments of the present invention can be designed to exhibit high tensile strength, compression properties (specifically, recovery after loading), an ability to be conformed to a variety of shapes and sizes, and/or any other suitable parameter. Within the knee joint there are two menisci: the lateral (outside of knee joint) and the medial (inside of knee joint). The dimensions for an adult meniscus vary for the lateral (approximately 33-36 mm in length and 26-29 mm in width) and medial (while the dimensions for the medial are 40-46 mm in length and ˜27 mm in width), with thicknesses ranging from 3-6 mm. Some embodiments of the present invention can be shaped to fit a variety of shapes while having regional variations in both tensile properties based on the in-plane variation of the courses and wales as well as compression properties. Fixation of the device in vivo may assist with its placement and performance, in some embodiments, and there are a variety of attachment mechanisms available. Fixations are based on tensioning load systems which can involve the drilling of a tunnel through the bone between the attachment point and an opposite surface, and/or suturing to the tibial plateau, and the additional use of tissue adhesives is also conceived. In some applications, it may be beneficial to replace the both the meniscus and the bone it is attached to. In addition to primary fixation, it is understood that in order to assist correct surgical placement the device could require a range of secondary fixation systems and include sutures pre-embedded into the device or guide sutures externally attached to it. Tension based fixation include fabric fixation points which are regions of either the first fabric, the second fabric, or a combination thereof which can act as suture attachments. Shear based fixation is comprised of fixating a fabric to the surrounding tissue and can include a fabric overlap to act as a plug to enhance the integration between the surrounding healthy tissue and the device. The fabric overlap can be substantially uniform around the circumference of the device, or in some regions of the fabric, the overlap can vary, with some regions having more and other regions having less of an overlap, or none at all. These devices can be used not only as a mechanical replacement for meniscus tissue, but also as a carrier for cells for potential regeneration.